This proposal examines potential mechanisms by which maternal and embryonic Zn deficiency arise, and how this deficiency results in abnormal development and growth. We will use pre-, peri-, and post-implantation embryo and cell culture techniques to confirm and extend results we obtain at the whole animal level. Embryo culture systems will allow us to study the influence of varying Zn concentration on the embryo during discrete periods of development. In addition, we will investigate the hypothesis that one mechanism by which an embryonic Zn deficiency can arise is due to a reduction in Zn transfer to the conceptus in cases where the mother has been subjected to a stressor which induces an acute phase response. According to this hypothesis, as part of the acute phase response there is an increase in the metallothionein concentration in maternal liver which results in a sequestration of Zn in the liver and concomitant hypozincemia. The hypozincemia results in a reduction in Zn transfer to the conceptus which presents a developmental risk. The above hypothesis will be tested using MT-knockout mice which we predict will show a reduced sensitivity to select teratogens. We suggest that embryonic Zn deficiency can lead to a compromised oxidant defense system, an increase in the concentration of reactive oxygen species (ROS), and resultant shifts in the redox state of cells. We suggest that Zn deficiency-associated cellular oxidative damage to lipid, protein and/or DNA contributes to the teratogenicity of Zn deficiency. We hypothesize that the altered redox states also results in the inactivation of oxidatively sensitive transcription factors such as NF-kappaB, and AP-1 and inactivation of Zn finger transcription factors GATA-4 and p53. It is predicted that an additional consequence of increased ROS in the embryo can be inappropriate and excessive apoptosis. Another mechanism for Zn deficiency-induced apoptosis is direct activation of caspase 3 protease that initiates the nucleolytic cascade of apoptosis. The down-regulation of growth factors and/or the functional blocking of growth factor signal transduction has also been demonstrates to result in apoptosis. Given that Zn deficiency can result in altered IGF metabolism, we hypothesize that a cell's ability to be rescued from apoptosis is reduced in Zn deficient embryos.